Phase separation underlies signaling activation of oncogenic NTRK fusions.

NTRK (neurotrophic tyrosine receptor kinase) gene fusions that encode chimeric proteins exhibiting constitutive activity of tropomyosin receptor kinases (TRK), are oncogenic drivers in multiple cancer types. However, the underlying mechanisms in oncogenesis that involve various N-terminal fusion partners of NTRK fusions remain elusive. Here, we show that NTRK fusion proteins form liquid-like condensates driven by their N-terminal fusion partners. The kinase reactions are accelerated in these condensates where the complexes for downstream signaling activation are also concentrated. Our work demonstrates that the phase separation driven by NTRK fusions is not only critical for TRK activation, but the condensates formed through phase separation serve as organizational hubs for oncogenic signaling.

Field experience with the 8-HPV-type oncoprotein test for cervical cancer screening among HPV-positive women living with and without HIV in LMICs.

Overexpression of HPV-oncoproteins E6 and E7 is necessary for HPV-driven cervical carcinogenesis. Hence, these oncoproteins are promising disease-specific biomarkers. We assessed the technical and operational characteristics of the 8-HPV-type OncoE6/E7 Cervical Test in different laboratories using cervical samples from HPV-positive women living with (WLWH) and without HIV. The 8-HPV-type OncoE6/E7 Test (for short: "OncoE6/E7 test") was performed in 2833 HIV-negative women and 241 WLWH attending multicentric studies in Latin America (ESTAMPA study), and in Africa (CESTA study). Oncoprotein positivity were evaluated at each testing site, according to HIV status as well as type-specific agreement with HPV-DNA results. A feedback questionnaire was given to the operators performing the oncoprotein test to evaluate their impression and acceptability regarding the test. The OncoE6/E7 test revealed a high positivity rate heterogeneity across all testing sites (I2: 95.8%, p < .01) with significant lower positivity in WLWH compared to HIV-negative women (12% vs 25%, p < .01). A similar HPV-type distribution was found between HPV DNA genotyping and oncoprotein testing except for HPV31 and 33 (moderate agreement, k = 0.57). Twenty-one laboratory technicians were trained on oncoprotein testing. Despite operators' concerns about the time-consuming procedure and perceived need for moderate laboratory experience, they reported the OncoE6/E7 test as easy to perform and user-friendly for deployment in resource-limited settings. The high positivity rate variability found across studies and subjectivity in test outcome interpretation could potentially results in oncoprotein false positive/negative, and thus the need for further refinements before implementation of the oncoprotein testing in screen-triage-and-treat approaches is warranted.

Impact of HPV strains on molecular mechanisms of cervix cancer.

PURPOSE: Cervical cancer accounts for a high number of deaths worldwide. Risk factors are extensive for cervix cancer but Human papillomavirus (HPV) plays a prime role in its development. Different strains of HPV are prevalent globally, which show different grades of mortality and morbidity among women. This study is planned to evaluate the molecular mechanism of different strains of HPV infection and progression leading to cervix cancer. METHODS: This review includes different research articles on cervix cancer progression reported from India and all over the world. RESULTS: HPV 16 and 18 are prevalent strains using heparan sulfate-independent and dependent pathways for viral replication inside the cell. It also uses transcription mechanisms through NF-kappa B, FOXA-1, and AP-1 genes while strains like HPV-35, 45, and 52 are also predominant in India, which showed a very slow mechanism of progression due to which mortality rate is low after their infection with these strains. CONCLUSION: HPV uses E6 and E7 proteins which activate NF-kappa B and AP-1 pathway which suppresses the tumor suppressor gene and activates cytokine production, causing inflammation and leading to a decrease in apoptosis due to Caspase-3 activation. In contrast, the E7 protein involves HOXA genes and decreases apoptotic factors due to which mortality and incidence rates are low in viruses that use E7 motifs. Some HPV strains employ the cap-dependent pathway, which is also associated with lower mortality and infection rates.

Oncogenic HPV promotes the expression of the long noncoding RNA lnc-FANCI-2 through E7 and YY1.

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3' untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.

Overexpression of the telomerase holoenzyme induces EMT and tumorigenesis of HPV-immortalized keratinocytes.

Cervical cancer is the most frequent malignancy of the female genital tract and is associated with persistent infection of the uterine cervix with high-risk human papillomaviruses (HPV). The two HPV oncoproteins, E6 and E7, cooperatively immortalize cervical cells and are essential but insufficient for inducing tumorigenicity. During the progression of HPV-associated cervical dysplasia to carcinoma, the cellular telomerase reverse transcriptase (TERT) gene is activated and the TERC gene amplified. We questioned whether these increases in telomerase components might mediate the acquisition of the tumorigenic phenotype. We therefore transduced the TERT and TERC genes into E6/E7 immortalized keratinocytes that were anchorage-dependent and nontumorigenic. The resultant cells showed a profound morphological change characteristic of epithelial-mesenchymal transition as well as a corresponding increase in expression of vimentin, N-cadherin, Zinc finger E-Box binding homeobox 1, snail family transcriptional repressor 1 and matrix Metallopeptidase 2 and decrease in keratin and E-cadherin. More important, the transduced cells were now anchorage-independent and formed tumors in immunodeficient mice. Our findings indicate that overexpression of the telomerase holoenzyme in HPV-immortalized cells is sufficient to induce the complete transformed phenotype.

Human papillomaviruses: Knowns, mysteries, and unchartered territories.

There has been an explosion in the number of papillomaviruses that have been identified and fully sequenced. Yet only a minute fraction of these has been studied in any detail. Most of our molecular research efforts have focused on the E6 and E7 proteins of "high-risk," cancer-associated human papillomaviruses (HPVs). Interactions of the high-risk HPV E6 and E7 proteins with their respective cellular targets, the p53 and the retinoblastoma tumor suppressors, have been investigated in minute detail. Some have thus questioned if research on papillomaviruses remains an exciting and worthwhile area of investigation. However, fundamentally new insights on the biological activities and cellular targets of the high-risk HPV E6 and E7 proteins have been discovered and previously unstudied HPVs have been newly associated with human diseases. HPV infections continue to be an important cause of human morbidity and mortality and since there are no antivirals to combat HPV infections, research on HPVs should remain attractive to new investigators and biomedical funding agencies, alike.

Molecular pathways in the development of HPV-induced oropharyngeal cancer.

Oropharyngeal cancer, a subset of head and neck cancer, is increasingly recognized as a unique clinical entity primarily influenced by high-risk human papillomavirus (HPV) infections, particularly HPV-16. This review delves into the viral life cycle of HPV-16 and its interactions with host cells, with a specific focus on the crucial roles played by the viral oncoproteins E6 and E7. These oncoproteins drive cellular proliferation by targeting critical tumor suppressor proteins like p53 and Rb, resulting in uncontrolled cell growth and genomic instability. Furthermore, the significance of epigenetic modifications induced by HPV-16 and their implications is important for cancer progression. This comprehensive review provides valuable insights into the intricate molecular landscape of HPV-induced oropharyngeal cancer, shedding light on the development of targeted therapies and preventive strategies for this emerging global health concern. Video Abstract.

Impacts of some clinicopathodemography and colorectal tissues key cell cycle and mucin stabilizing molecules on the metastasis trend in colorectal cancer patients.

BACKGROUND: We aimed to evaluate the various clinicopathodemographical, epidemiological, and molecular contributors to cumulatively worldwide metastatic colorectal cancer (CRC) in CRC patients from a highly populated area in northeastern Iran to pinpoint metastasis risk. METHODS: A retrospective clinical material-based cohort including a total of 6260 registered CRC patients, of whom 3829 underwent surgery, from regional university hospitals, during 2006-2016, were analyzed for the clinicopathodemographical aspects of age, sex, stage of CRC, history of smoking, type 2 diabetes (T2D), hypertension, body mass index (BMI), familial/occupational status, post-surgery survival period and mRNA/protein expression of mucin stabilizer (B3GALNT2), mucin I (MUC1), key cell cycle molecules (i.e., P53 and Ki67), and MMR-related genes. Factors were set to estimate the risk of metastatic CRC and mortality. RESULTS: Predominant adenocarcinomatous CRCs were found in colon. Post-surgery survival period of metastatic CRC patients was remarkably longer in patients aged > 50 compared to those aged < 50 years, and worse in females than males. B3GALNT2high, MUChigh, P53low, and Ki67high mRNA/protein expression in the metastatic stage III CRC along with T2D and hypertension were associated with increased metastasis/mortality, with more worsening in males, older, BMI > 25, urban residing, and employed individuals, indicative of non-genetic attributable factors. CONCLUSION: B3GALNT2, MUC1, and "Ki67" can be used as promising biomarkers for prognosis and early diagnosis of increasingly/predominantly non-genetic/environmental originated metastatic CRCs.

Oncogenic Viruses and the Epigenome: How Viruses Hijack Epigenetic Mechanisms to Drive Cancer.

Globally, viral infections substantially contribute to cancer development. Oncogenic viruses are taxonomically heterogeneous and drive cancers using diverse strategies, including epigenomic dysregulation. Here, we discuss how oncogenic viruses disrupt epigenetic homeostasis to drive cancer and focus on how virally mediated dysregulation of host and viral epigenomes impacts the hallmarks of cancer. To illustrate the relationship between epigenetics and viral life cycles, we describe how epigenetic changes facilitate the human papillomavirus (HPV) life cycle and how changes to this process can spur malignancy. We also highlight the clinical impact of virally mediated epigenetic changes on cancer diagnosis, prognosis, and treatment.

Bacterial Species from Vaginal Microbiota Differently Affect the Production of the E6 and E7 Oncoproteins and of p53 and p-Rb Oncosuppressors in HPV16-Infected Cells.

Vaginal dysbiosis is characterized by a decrease in the relative abundance of Lactobacillus species in favor of other species. This condition facilitates infections by sexually transmitted pathogens including high risk (HR)-human papilloma viruses (HPVs) involved in the development of cervical cancer. Some vaginal dysbiosis bacteria contribute to the neoplastic progression by inducing chronic inflammation and directly activating molecular pathways involved in carcinogenesis. In this study, SiHa cells, an HPV-16-transformed epithelial cell line, were exposed to different representative vaginal microbial communities. The expression of the HPV oncogenes E6 and E7 and the production of relative oncoproteins was evaluated. The results showed that Lactobacillus crispatus and Lactobacillus gasseri modulated the basal expression of the E6 and E7 genes of SiHa cells and the production of the E6 and E7 oncoproteins. Vaginal dysbiosis bacteria had contrasting effects on E6/E7 gene expression and protein production. The expression of the E6 and E7 genes and the production of the relative oncoproteins was increased by strains of Gardnerella vaginalis and, to a lesser extent, by Megasphaera micronuciformis. In contrast, Prevotella bivia decreased the expression of oncogenes and the production of the E7 protein. A decreased amount of p53 and pRb was found in the cultures of SiHa cells with M. micronuciformis, and accordingly, in the same cultures, a higher percentage of cells progressed to the S-phase of the cell cycle compared to the untreated or Lactobacillus-stimulated cultures. These data confirm that L. crispatus represents the most protective component of the vaginal microbiota against neoplastic progression of HR-HPV infected cells, while M. micronuciformis and, to a lesser extent, G. vaginalis may directly interfere in the oncogenic process, inducing or maintaining the production of viral oncoproteins.

Enhanced Intracellular Photosensitizer Uptake and Retention by Targeting Viral Oncoproteins in Human Papillomavirus Infected Cancer Cells and Cancer Stem Cells.

Immunogenic proteins in cancer are relevant targets for drug delivery. In Photodynamic Therapy (PDT), surface antigens have previously been used to deliver the photosensitizer (PS) to the tumor microenvironment for specific targeting. However, can we target intracellular antigens to achieve more than surface recognition? Can we possibly increase PS intracellular localization and prevent drug efflux at the same time? In this study, these questions were addressed by using a compound that can not only specifically recognize and bind to intracellular E6 oncoproteins in Human Papillomavirus (HPV)-Transformed cancer cells, but is also capable of enhancing transmembrane uptake using the cells' own active transport mechanisms. HPV-transformed SiHa cells were cultured in vitro, and the resistant subpopulation was isolated using Magnetic Activated Cell Sorting (MACS). PDT was performed on four different cell types with varying physiognomies in terms of HPV oncoprotein expression and physiological form. Results demonstrated that tagging PSs on a carrier molecule that specifically delivers the PS inside the cells that express the target proteins enhanced both cellular uptake and retention of the PS even in the presence of drug efflux proteins on resistant subpopulations. These findings provide insight into the possibility of preventing cell-mediated resistance to PDT.

Two conserved amino acids differentiate the biology of high-risk and low-risk HPV E5 proteins.

The high-risk alpha human papillomaviruses (HPVs) are responsible for 99% of cervical cancers. While the biological functions of the HPV E6 and E7 oncoproteins are well-characterized, the function of E5 has remained elusive. Here, we examined gene expression changes induced by E5 proteins from high-risk HPV-16 and low-risk HPV-6b in multiple pools of primary human keratinocytes. Surprisingly, microarray analysis revealed that over 700 genes were significantly regulated by HPV-6b E5, while only 25 genes were consistently and significantly regulated by HPV-16 E5 in three biological replicates. However, we observed that more than thousand genes were altered in individual sample compared with vector. The gene expression profile induced by 16E5 in primary genital keratinocytes was very different from what has been previously published using immortalized HaCaT cells. Genes altered by HPV-16 E5 were unaffected by HPV-6b E5. Our data demonstrate that E5 proteins from the high- and low-risk HPVs have different functions in the HPV-host cell. Interestingly, conversion of two amino acids in HPV-16 E5 to the low-risk HPV-6b sequence eliminated the induction of high-risk related cellular genes.

AIB1 is a novel target of the high-risk HPV E6 protein and a biomarker of cervical cancer progression.

The high-risk human papillomaviruses (HPV-16, -18) are critical etiologic agents in human malignancy, most importantly in cervical cancer. These oncogenic viruses encode the E6 and E7 proteins that are uniformly retained and expressed in cervical cancers and required for maintenance of the tumorigenic phenotype. The E6 and E7 proteins were first identified as targeting the p53 and pRB tumor suppressor pathways, respectively, in host cells, thereby leading to disruption of cell cycle controls. In addition to p53 degradation, a number of other functions and critical targets for E6 have been described, including telomerase, Myc, PDZ-containing proteins, Akt, Wnt, mTORC1, as well as others. In this study, we identified Amplified in Breast Cancer 1 (AIB1) as a new E6 target. We first found that E6 and hTERT altered similar profiling of gene expression in human foreskin keratinocytes (HFK), independent of telomerase activity. Importantly, AIB1 was a common transcriptional target of both E6 and hTERT. We then verified that high-risk E6 but not low-risk E6 expression led to increases in AIB1 transcript levels by real-time RT-PCR, suggesting that AIB1 upregulation may play an important role in cancer development. Western blots demonstrated that AIB1 expression increased in HPV-16 E6 and E7 expressing (E6E7) immortalized foreskin and cervical keratinocytes, and in three of four common cervical cancer cell lines as well. Then, we evaluated the expression of AIB1 in human cervical lesions and invasive carcinoma using immunohistochemical staining. Strikingly, AIB1 showed positivity in the nucleus of cells in the immediate suprabasal epithelium, while nuclei of the basal epithelium were negative, as evident in the Cervical Intraepithelial Neoplasia 1 (CIN1) samples. As the pathological grading of cervical lesions increased from CIN1, CIN2, CIN3 carcinoma in situ and invasive carcinoma, AIB1 staining increased progressively, suggesting that AIB1 may serve as a novel histological biomarker for cervical cancer development. For cases of invasive cervical carcinoma, AIB1 staining was specific to cancerous lesions. Increased expression of AIB1 was also observed in transgenic mouse cervical neoplasia and cancer models induced by E6E7 and estrogen. Knockdown of AIB1 expression in E6E7 immortalized human cervical cells significantly abolished cell proliferation. Taken together, these data support AIB1 as a novel target of HPV E6 and a biomarker of cervical cancer progression.

Immune cells markers within local tumor microenvironment are associated with EBV oncoprotein in nasopharyngeal cancer.

INTRODUCTION: EBV infection in nasopharyngeal cancer ensued in latent infection mode. In this latent infection various EBV oncoproteins such as EBNA1 and LMP1 was expressed. EBV oncoproteins could theoretically recruit immune cells, which might help to control cancer. Therefore, this study was aimed to elucidate the association with EBV oncoproteins (EBNA1 and LMP1), immune markers (CD4, CD8, and FOXP3) from nasopharyngeal cancer microenvironment with tumor progression. METHOD: Nasopharyngeal biopsy was obtained from patients suspected to have nasopharyngeal cancer. Those samples with microscopically confirmed nasopharyngeal cancer were tested for EBNA1, LMP1, CD4, CD8, and FOXP3 concentration with ELISA, then verified with IHC. Each patient tumor volume was assessed for primary nasopharyngeal tumor volume (GTVp) and neck nodal metastases tumor volume (GTVn). Correlation test with Spearman correlation and scatterplot were carried out. RESULT: Total 23 samples with nasopharyngeal cancer were analyzed. There was moderate correlation (ρ = 0.45; p value = 0.032) between LMP1 and GTVp. There was strong correlation (ρ = 0.81; p value < 0.001) between CD8 and GTVp. There was also moderate correlation (ρ = 0.6; p value = 0.002) between FOXP3 and GTVp. The CD8 concentration has moderate correlation with both EBNA1 (ρ = 0.46; p value = 0.026) and LMP1 (ρ = 0.47; p value = 0.023). While FOXP3 has moderate correlation with only LMP1 (ρ = 0.58; p value = 0.004). No correlation was found between all the markers tested here with GTVn. DISCUSSION: We found larger primary nasopharyngeal tumor was associated with higher CD8 marker. This was thought due to the presence of abundance CD8 T cells in the nasopharynx, but those abundance CD8 T cells were suspected to be dysfunctional. The nasopharyngeal cancer was also known to upregulate chemokines that could recruit T regulatory FOXP3 cells. Furthermore, T regulatory FOXP3 cells differentiation was induced through several pathways which was triggered by EBNA1. The correlation found in this study could guide further study to understand nasopharyngeal carcinogenesis and the relationship with our immune system.

The Importance of Small Extracellular Vesicles in the Cerebral Metastatic Process.

Brain metastases represent more than 50% of all cerebral tumors encountered in clinical practice. Recently, there has been increased interest in the study of extracellular vesicles, and the knowledge about exosomes is constantly expanding. Exosomes are drivers for organotropic metastatic spread, playing important roles in the brain metastatic process by increasing the permeability of the blood-brain barrier and preparing the premetastatic niche. The promising results of the latest experimental studies raise the possibility of one day using exosomes for liquid biopsies or as drug carriers, contributing to early diagnosis and improving the efficacy of chemotherapy in patients with brain metastases. In this review, we attempted to summarize the latest knowledge about the role of exosomes in the brain metastatic process and future research directions for the use of exosomes in patients suffering from brain metastatic disease.

A phase 1, single centre, open label, escalating dose study to assess the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) for HPV-associated head and neck cancer (HNC).

BACKGROUND: We conducted a phase 1 dose escalation study (ACTRN12618000140257 registered on 30/01/2018) to evaluate the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) in subjects previously treated for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Eligible subjects had to have no evidence of recurrent and/or metastatic disease at least 12 weeks following the completion of treatment. Three dosing cohorts each consisted of four subjects: group 1: 0.25 mg/dose, group 2: 1 mg/dose, group 3: 4 mg/dose. AMV002 was delivered intradermally on days 0, 28 and 56. Incidence and severity of treatment-emergent adverse events (TEAE) including local reaction at the injection site, and vaccination compliance were recorded. T cell and antibody responses to HPV16 E6 and E7 were measured by interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay and enzyme-linked immunosorbent assay (ELISA). RESULTS: All subjects completed the vaccination programme and experienced mild discomfort at the injection site(s). Pre-immunisation, cell-mediated responses to HPV16 E6 and E7 were evident in all subjects, and E7-specific antibodies were detected in 11 (91.7%), reflecting previous exposure to HPV. Post-vaccination, 10 of 12 (83.3%) subjects responded to one or more of the E6 and/or E7 peptide pools, while 2 (16.7%) did not show additional vaccine-induced cell-mediated responses. Vaccination resulted in a ≥ 4-fold increase in anti-HPV16 E7 antibody titre in one subject in group 3. CONCLUSIONS: AMV002 was well tolerated at all dose levels and resulted in enhanced specific immunity to virus-derived tumour-associated antigens in subjects previously treated for HPV-associated OPSCC.

Genetic variability of the HPV16 early genes and LCR. Present and future perspectives.

Human papillomavirus 16 (HPV16) infection is the aetiologic factor for the development of cervical dysplasia and is regarded as highly carcinogen, because it is implicated in more than 50% of cervical cancer cases, worldwide. The tumourigenic potential of HPV16 has triggered the extensive sequence analysis of viral genome in order to identify nucleotide variations and amino acid substitutions that influence viral oncogenicity and subsequently the initiation and progression of cervical cancer. Nowadays, specific mutations of HPV16 DNA have been associated with an increased risk of high-grade squamous intraepithelial lesions and invasive cervical cancer (ICC) development, including E6: Q14H, H78Y, L83V, Ε7: N29S, S63F, E2: H35Q, P219S, T310K, E5: I65V, whereas highly conserved regions of viral DNA have been extensively characterised. In addition, numerous novel HPV16 mutations are observed among the studied populations from various geographic regions, hence advocating that different HPV16 strains seem to emerge with different tumourigenic capacities. The present review focuses on the variability of the early genes and the long control region, emphasising on the association of specific mutations with the development of severe dysplasia. Finally, it evaluates whether specific regions of HPV16 DNA are able to serve as valuable biomarkers for cervical cancer risk.

Beta human papillomaviruses infection and skin carcinogenesis.

During the last decade, the worldwide incidence of keratinocyte carcinomas (KC) has increased significantly. They are now the most common malignancy, representing approximately 30% of all cancers. The role of ultraviolet (UV) radiation as a major environmental risk factor for skin cancers is well recognized. The aim of this review is to analyse the current understanding of the nature of beta-human papillomavirus (HPV) and its association with KC and explore the implications for the management and prevention of these cancers. A comprehensive review of the literature on beta-HPV and its association with KC was undertaken, the results reported in the form of a narrative review. A subgroup of HPV that infects the mucosal epithelia of the genital tract has been firmly associated with carcinogenesis. In addition, some HPV types with cutaneous tropism have been proposed to cooperate with UV in the development of KC. The first evidence for this association was reported in 1922 in patients with epidermodysplasia verruciformis (EV). Since then, epidemiological studies have highlighted the higher risk of skin cancer in patients with EV and certain cutaneous HPV types, and in vitro studies have elucidated molecular mechanisms and transforming properties of beta-HPV. Furthermore, in vivo research conducted on transgenic mice models has shown the possible role of beta-HPV in cutaneous carcinogenesis as a co-factor with UV radiation and immunosuppression. There is good evidence supporting the role of beta-HPV in the oncogenesis of KC. The high prevalence of beta-HPV in human skin and the worldwide burden of KC makes the search for an effective vaccine relevant and worthwhile.

Virus against virus: strategies for using adenovirus vectors in the treatment of HPV-induced cervical cancer.

Although most human papillomavirus (HPV) infections are harmless, persistent infection with high-risk types of HPV is known to be the leading cause of cervical cancer. Following the infection of the epithelium and integration into the host genome, the oncogenic proteins E6 and E7 disrupt cell cycle control by inducing p53 and retinoblastoma (Rb) degradation. Despite the FDA approval of prophylactic vaccines, there are still issues with cervical cancer treatment; thus, many therapeutic approaches have been developed to date. Due to strong immunogenicity, a high capacity for packaging foreign DNA, safety, and the ability to infect a myriad of cells, adenoviruses have drawn attention of researchers. Adenovirus vectors have been used for different purposes, including as oncolytic agents to kill cancer cells, carrier for RNA interference to block oncoproteins expression, vaccines for eliciting immune responses, especially in cytotoxic T lymphocytes (CTLs), and gene therapy vehicles for restoring p53 and Rb function.

Targeting Human Papillomavirus-Associated Cancer by Oncoprotein-Specific Recombinant Antibodies.

In recent decades, recombinant antibodies against specific antigens have shown great promise for the therapy of infectious diseases and cancer. Human papillomaviruses (HPVs) are involved in the development of around 5% of all human cancers and HPV16 is the high-risk genotype with the highest prevalence worldwide, playing a dominant role in all HPV-associated cancers. Here, we describe the main biological activities of the HPV16 E6, E7, and E5 oncoproteins, which are involved in the subversion of important regulatory pathways directly associated with all known hallmarks of cancer. We then review the state of art of the recombinant antibodies targeted to HPV oncoproteins developed so far in different formats, and outline their mechanisms of action. We describe the advantages of a possible antibody-based therapy against the HPV-associated lesions and discuss the critical issue of delivery to tumour cells, which must be addressed in order to achieve the desired translation of the antibodies from the laboratory to the clinic.